Carbamazepine has the formula and is a valuable agent for treating the central nervous system, such as an anticonvulsant, or to produce analgesia.
Processes for producing carbamazepine are known for example from U.S. Pat. No. 2,948,718, European patent No. 423,679, and German (East) patent Nos. 297,962 and 298,508, which disclose reacting iminostilbene with phosgene to produce 5H-dibenz[b,f]azepine-5-carboxylic acid chloride, followed by the addition of ammonia.
From British patent No. 1,246,606 it is known to produce carbamazepine 10,11-dihydro-5H-dibenz[b,f]azepine seriatim with phosgene, 1,3-dibromo-5,5-dimethyl-hydan-toin, then potassium carbonate, and ammonia.
Another method for the production of carbamazepine is known from German published patent application No. 2,307,174 by the reaction of iminostilbene with an acylisocyanate to produce 5H-dibenz[b,f]azepin-5-(N-acyl)-carboxamide followed by hydrolysis. German published patent application No. 2,637,666 discloses the reaction of 5-(methylisothiocarbamoyl)-5H-dibenz[b,f]azepine-hydroiodide with a base.
European patent No. 29,409 discloses the acid or alkaline hydrolysis of 5-cyano-5H-dibenz[b,f]azepine.
All of the aforementioned known processes have a variety of drawbacks. For example, many known processes require the use of the highly toxic phosgene or halogen cyanide. In the process according to German published patent application No. 2,307,174 the use of unstable and generally unavailable acylisocyanates is required. In the process of German published patent application No. 2,637,666 toxic methylmercaptan is a byproduct.
Carbamazepine can be, furthermore, also produced by reaction of iminostilbene with hydrogen cyanide in an organic solvent or solvent mixture in the presence of an acidifier as described in European patent No. 277,095. The acidifier has only a catalytic role and increases the conversion rate of the iminostilbene and the cyan-hydroxide. The latter is introduced into the reaction mixture as a gas, but can also be recovered by reacting a cyanide salt with an acid.
Since the hydrogen cyanide enters into undesired side reactions with water, alcohols, and amines, the reaction is to be carried out under strongly aprotic conditions in solutions which are substantially free of water, alcohol and amines, and without the use of water vapors. Such conditions make the entire process very difficult and require additional materials and special procedures.